Pharmaceutical manufacturers employ several forms for therapeutic compound delivery. For example, a liquid form may be used for injectable or ingestible therapeutic compounds. Ingestible compounds also may be delivered through tablets, capsules, and gelcaps. It is common in the manufacture of each of these forms of therapeutic compound delivery to require discrete analysis of samples of the therapeutic compound delivery form. This analysis is presently performed in a quality assurance laboratory located away from the manufacturing area. Such “off-line” analysis often is expensive and inefficient.
To illustrate the inefficiency of off-line quality assurance analysis, consider the manufacture of the tablet form of therapeutic compound delivery. During manufacture of tablets, a pharmaceutical tablet press operates on a therapeutic compound, normally in the form of a powder. The tablet press compresses the therapeutic compound into a tablet for subsequent ingestion and delivery of the therapeutic compound. Optionally, a binding agent may be added to the therapeutic compound during manufacturing to enhance tablet formation. Automated tablet presses may be employed to create tablets very quickly. Many automated tablet presses are capable of producing in excess of ten thousand tablets per minute.
After manufacture, it is typical that a representative sample of the tablets from each manufactured lot is taken to a separate quality assurance laboratory for analysis. Testing of the sample tablets ordinarily occurs after all tablets in a manufactured lot have been created, to permit a representative sample to be selected for analysis. The quality assurance laboratory conducts tests on the tablets to determine, for example, the chemical composition, variability, and other data from the sample tablets. The data collected from the tests is analyzed, and if the sample tablets are found to be within the manufacturer's specifications, the balance of the lot of manufactured tablets are released for packaging and use. If the sample tablets are not found to satisfy the manufacturer's specifications, it frequently is necessary to scrap the entire manufactured lot of the tablets.
During the time the sample tablets undergo testing in the quality assurance laboratory, the balance of the manufactured tablets from the lot are waiting in inventory storage. Without assurance that the tablets are within the manufacturer's specifications, releasing the balance of the manufactured tablets from the lot for packaging would present an unacceptable risk, as well as potentially wasting expensive packaging materials and labor. In addition, in some cases the manufacturing apparatus on which the tablets were produced may not be used again until a manufactured lot has received clearance from the quality assurance laboratory. Failure of the sample tablets to meet the manufacturer's specifications may be indicative of a problem with the manufacturing apparatus, or with the overall manufacturing process.
Unfortunately, off-line testing of pharmaceutical products in a quality assurance laboratory frequently introduces a bottleneck into the manufacturing process. The tests conducted by a quality assurance laboratory usually require the sample tablets to be prepared for testing with a great deal of human intervention. The time spent preparing the sample tablets for quality assurance testing may be several orders of magnitude longer than the time spent manufacturing the tablets.
At present, two methods are most commonly used for off-line sample testing, a spectroscopic method and a wet method. The spectroscopic method emits radiation onto a sample, and analyzes radiation emitted or reflected by the sample. The spectroscopic method may be non-destructive, or may destroy or degrade the tablet, depending on the wavelength and intensity of the radiation used. The wet method involves dissolving the sample in a solvent, or mixing the sample with other chemicals. The wet method is always destructive of the sample.
In addition to the sample preparation time required, the sample tablets may also wait in a queue while the off-line quality assurance laboratory conducts testing on other manufactured lots. Ultimately, the off-line testing process may add days or weeks to the manufacturing cycle time for each lot of tablets, through time directly spent testing the tablets, or time the sample tablets spend in queue. During this time, the balance of the manufactured tablets from the lots is held in storage, and the entire manufacturing process may be stopped, both of which can result in a significant loss of potential profit.
Further, even if the number of sample tablets selected for quality assurance testing is statistically appropriate, selectively testing only a subset of tablets taken from a larger group always incurs a risk that a problem may be overlooked. However, because the tests conducted on the sample tablets by the quality assurance laboratory ultimately results in the destruction of the tablets in many cases, it would be impossible to conduct testing on all of the manufactured tablets using common methods. The risk may be reduced by testing a greater number of the tablets, but the point at which destructive testing is economically infeasible is reached well before a one hundred percent sampling of the overall manufactured lot occurs.
Of course, the bottleneck presented by the off-line quality assurance laboratory is not limited to the manufacture of tablets. Gelatin capsules, topical ointments, and liquids are just a few possible forms of delivery of therapeutic compounds. In each case, representative samples are taken from the manufacturing process, and off-line testing is performed by a quality assurance laboratory. Therefore, it is possible that the manufacturing process for each method of therapeutic compound delivery suffers from the same or similar limitations as that experienced by the off-line analysis of tablets in a quality assurance laboratory.
For all the foregoing reasons, there is a need in the art for a system having the ability to analyze samples of pharmaceutical products in real time and in a way that is integrated with the manufacturing process. Such a system will conduct the analysis in a non-destructive manner, and will be adaptable to test each tablet produced by the manufacturing process, thereby reducing the statistical risk incurred by testing only a subset of the tablets. Alternatively, an enhanced statistical sampling could be conducted based on the information received by the system. By sampling “in-process” and in real time, process problems or manufacturing apparatus problems may be identified and fixed without requiring an entire lot to be created, thereby reducing costs.
Such a system may be used in conjunction with a traditional quality assurance laboratory. Routine testing could be done in real time using the desired system, and the quality assurance laboratory could be used to check smaller samples, to verify the correct operation of the system. Also, the desired system will provide a sufficient level of testing so that the balance of tablets from a manufactured lot may be more quickly released for packaging, and the manufacturing apparatus may be more quickly brought back into productive use, while previous lots wait in the queue or undergo analysis by the off-line quality assurance laboratory. Reducing cycle time in this critical stage of manufacturing results in less downtime, and an increase in productivity and profitability.